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Aug. 25, 1953 J. H. 'r. LEDRUT 2,650,219

REACTION PRODUCT 0F ANTIPYRINE ALDEHYDE P AMINOBENZENE; SULFONAMIDE ANDSODIUM BISULFITE Filed se su .18, 1950' INVENTOR- -H' T. LE [3 RUT mm,km 1 9mm a W e Patented Aug.

UNITED STATES FATENT oFFIoE naao'ri'on rnonuor OEANTIBYRINE 11 DE,p-AMINOBENZENE SULFONAMIDE, AND SODIUM BISULFITE fle i ThedllhileLedlllt, Brussels liel i i fij;

assignor to Luxeina S. A., lxelles, Belgium; 1: company of LuxemburgApplication September 18, i550, Serial 6. In the Netherlands September20, 1949' 1 Claim. (01. 260 -2393) The present invention" relates to newcompounds, obtained from altrisubstituted pyrazolone aldehyde, a primaryamine selected from the class consisting of the morioeyclicand bicyclicprimary amines, and sodium bisulfite. r,

The new compounds according to the invention have the following generalformula:

in which R is a radical selected from the class consisting of themethylradical and the phenyl radical, R is a monocyclic aryl radical and R isa radical selected from the: class consisting of the monocyclic andbicyclic radicals having at least five carbon atoms.

It is known h t-th alde avd r9 l fi-fi i u stituted pyrazolonesand-specially; the aldehyde of 1-phenyl-2,3 -dimethyl pyraaolone orantipyrine h e rean i he micnp p r ies- Moreover, ls nowntHaQiQQPeIa-aMn r benzene sulf onamide has ,loacteriostaticpropertieswith respect to certain microorganisms, such as Streptococcus,Staphylococcusetc.

Various derivatives have been prepared from the 1,2,3-trisubstitutedpyrazolgnes Th e pharmacodynamio properties of ti ese lgnovvnderivatives were examined. Amongst these derivatives, the1-phenyl-2,3-dimethyl 4 sulfonamido 5- pyrazolone was particularlystudiedisee. E. H. Northey, The Sulfonamides and Allied Compounds, 1948,p.- 260, ReinholdPubl. Corporation). It was found that this latterderivative does no more possess the antithermic properties ofantipyrine, nor the bacteridsta'tic properties of the sulfonamide.

The bisulfite compounds- 0fthe schifis bases of 1,2,3-trisubstitutedpyra'zolone; obtained according to the present invention, haveantither'm'ic and bacteriostatic properties.

For example; the bisulphite compound offthe Schiifs base obtainedbyTea'Eting," in equimolecu lar proportions, antipyrine aldehydewith'para amino-benzene sulfonar'nide and sodium" bisub 2 phite,possesses very marked antitherrni'c' and bacteriostatic pr'pertiejs.1 Ia Th s o bu ha in e fol owi n a formula I 1. Antithermie propertiesDoses of 1 a. and 0.5 grj. of the bisulphite compara amino-benz'enesulfonamide, were orally cine, eontammg'a'ttenuat'ed strainsofstreptococ' cus, Staphylococcus and pyocyanic Bacillus and frequentlyused in order to create experimental hyperthermic conditions.

The annexed diagram shows the observed re-'- sults. On this diagram; thetime (in hours) aftenthe administration of the abovementioned bisulphitecompund is plotted against the valiationsof the telnperaturef of theexamined dogs. The origin ofthe ordinates corresponds to the t edosa lif-er the dm n t aite compound. i

eiifll n il v i h s hei riatiensi ftn temperature" of a dog, to which adose, as here n fied, of Prjopidon was administered yvithout anysubsequent administration of thebisulphitecompound. a

The dash a dot' line curve shows, the variations ofthe' -tempra nirdfadogj to which were successively administered a dose of Propi'doi iFinally, the dashline curve shows nons of the temperature or adtjg, t6 wsuccessively administered the saints Propiddn an'dl'gr.orthe-bisfilphitbbln* As shown by these curves, the bisulph" e s, H .91poundmhibitsgreatly the hyperthermic conditions built up by theadministration of Propidon.

2. Bacteriostatic properties 3. A 1% solution of para-amino-benzenesulfonamide in ordinary meat-broth.

All these solutions were sterilized on a Zeiss filter. limit of thetests, as the 1% para-amino-benzene sulfonamide solution is a saturatedsolution.

At a concentration of 0.62%, the antipyrin aldehyde does not inhibit'thegrowth of the tested species, whereby this latter compound may beconsidered as being free of any effect on the results indicated in thefollowing table:

. Sensitivity of the Species Used Species Remarks Streptococcus viridans9601 no The species grows in the presence of 1% sulfanilamide orbisulphite compound. Anhemolytic 85a5.- no dem. Hemolytic Hop no idem.Viridans Hop yes The growth is 1nhibited 1n the presence of 7%sulfanilamide and 5% bisulphite compound. Enterococcus 8521 no Thespecies grows in the presence of 1 amide or bisulphite compound.Pneumococcus Hop yes The sensitivity of the species is very high, butthe lower limit is not clearly defined.

Pyocyanic Bacillus Hop yes even in the presence of a com- 1% bisulphitepound, the growth of the species is completely inhibited. Staphylococcuspus X no Normal growth in the presence of 1% sulfanilamide or bisulphitecompound. pus M26 no idem. pus D26 yes The species grows in the presenceof 1% sulfanilamide, but growth is inhibited in the presence of 0.5 to1% bisulphite compound. pus 96m yes dem. white Hop. dem.

idem.

In the presence of 7% bisulphite compound, the growth is inhibited,whereas 8% sulfanilamide are necessary to inhibit the growth.

As a rule, the abovementioned bisulphite compound may be considered asmore active on the sensitive species than the para-amino-benzenesulfonamide.

In vitro, the said bisulphite compound has an activity about three timesgreater than that of the sulfonamide alone, in the same experimentalconditions. 7

Some methods of carrying out the preparation %sulianil- Theconcentration of 1% was the actual of bisulphite compounds of1,2,3-trisubstituted pyrazolones Schiffs base will now be described. Theexamples given are merely illustrative and are not to be construed aslimiting the present invention.

Examples 1 to 13 describe the preparation of Schiffs bases from1,2,3-trisubstituted pyrazolones and a primary amine.

The reaction for the production of these Schiffs bases may berepresented, as follows:

UH -1 T :0

1,2,3-trlsubstituted ,Prlmery pyrazolone aldehyde l amine R-C ---GC H20I CHaN 0:0 NR

Schifis base In the above indicated formulae, R, R, B have theabovementioned meanings.

Example 1 V 9.9 gr. of cyclohexylamine are mixed with 1.6 gr. of1-phenyl-2,3-dimethyl-5-pyrazolone aldehyde and 1 gr. of potassiumcarbonate. After heating during 30 minutes on a water bath, crystals areobtained, which are centrifuged and recrystallised from ethyl alcohol.These crystals melt at 148 C.

The Schiifs bas obtained has the formula C1'1H23ON2. The quantitativeanalysis of this Schifis base gives the following results, compared withthe theoretical:

o H i N Calculated 72.69 7. 7e .13 Found 72. e2 7. 7 14. 4e

Example 2 o 11 N M. w.

Calculated 74.22 cos 14. 4 5 280 Found.- 74.20 5.88 14.43 291 Example 326.2 gr. of 1,3-diphenyl-2-methyl5-pyrazolone aldehyde are heated with9.3 gr. freshly distilled aniline, in the presence of 5 gr. of drypotassium carbonate. One proceeds subsequently as described in Example.2.

The Schiffs base obtained has the formula C23H19ON3 and melts at C. Itcontains 12.17% 'of nitrogen, whereas the theoretical amount ofnitrogenis11.89%.' i

Earampled 10.7 gr. of orthO-tOliiidiiie are. vigorously mixed with 21.6gr. of 1-phenyl-2,-difiiethyl-5epyrazo amounts to 75%. r i

The, Schifis base obtained has, the-formula C19H19ON3 and melts atl9,2G.

The quantitati e analysisgiyes' the following results,comparedwiththetheoretical:

Calculated 74.45 6:22" 13.77 305 Found 74: 56 6,351: 13. 79. a

Emample 14.4 gr. of naphthylamine are mixed with 21.6 gr. of1-phenyl-2,3-dimethyl-5-pyrazolone aldehyde. After addition of. ethyl.alcohol; in order to obtain a complete dissolution,thesolutioniobtamedis heated; nderreflux; during: 2;. hours.

Examplet 2.16 gr. of 1-phenyl-2,3rdimethyl-5-pyrazolone are dissolved in1.0. cc. ethyl. alcohol. To the solution obtained are. added- 1.53,=.gr. of paraamino salicylic, acid dissolved, in 10, 00.. ethylx al cohol.By. mixing. the two. aboveernentioned solutions, without heating,afreezing is obtained. The freezed mass is then heated during A; hourExample 7 1.8 gr. of 1-phenyl-2,3 dimethyl-5-pyrazolone aldehyde aredissolveddn 15" cc. of water.-; To

without heating, a salt is. obtained which. melts at 190 C. Bysubsequenthea'ting, the .S'chifis base melting at 265-267"C:" isobtained.

Example 8" 2.016 gr. of 1 phenyl-2,3-dimethyl- 5 pyrazole one are mixedwith A0!) mol. of para--amino'- benzoic acid. The crystallineprecipitate ob-- tained is centrifuged .-and., recrystallised. fromethyl alcohol. The SchiiTs base obtained melts at 200 C. i i 1 Example 910.9 gr. of para-amino-phenol are dissolved in ethyl alcohol. To thesolution obtained is added pyrine aldehyde. The two mixed solutions areheated under reflux during two hours. After cooling, the yellow crystalsobtained are centrifuged and recrystallised from ethyl alcohol. Thesecrystals melt at 232-233 C. The Schiifs base obtained has the formulaC'mHnOzNs.

The quantitative analysis gives the following results, compared with thetheoretical:

Example 10 13.6 gr. of' para-phenetidine, 21.6 gr. of 1-pheny1-2,3-dimethyFS-pyrazolone aldehyde and 10 gr. of potassiumcarbonate are mixed and heated. during two hours. After cooling, thecrystals obtained are centrifuged and recrystallised from ethyl alcohol.

The Schifis base" obtained has the empirical formula C10H2102N3 andmelts at 163 CL Thequantitativeanalysis of this Sch'ifisbase gives thefollowing results, compared with" t theoretical o H N M. w.

Calculated 71. 64 6.27 i 12. 53 1 335 FOllIld 71. 26 (2141 12. 43 338Example 1 1.

Equixnolecularf quantities of 4-amino'aritipy rine and antipyrinaldehyde are heated? In 'the presence of ethyl alcohol the Schiffis"base precipitates. The crystals obtained are centrifuged and.recrystallisedlfrom ethyl alcohol The Schiffs base obtained has the:formula C23H2702N5 and meltsrat 224 425 CL The quantitative analysis" ofthis Schiifs'base gives the following results, compared with thetheoretical i (lalculatedluflo 68982 i Found 68.9? 6.00

sulphite compounds, according to the Examples.

12 and 13, may be represented asfoll'ows:

H R O-- =C-'O-'/I-OH.

fsoaNa RNH2 Bisulphite compound of 1,2,3- trisubstituted pyrazolonealdehyde l C HPN lrimar'i amine Example 12 3.20 gr. of the bisulphitecompound of 1-phen-- yl-2,3-dimethyl-5-pyrazolone aldehyde are dissolved in 20 cc. of cold water. To the solution obtained are added,while mixing and dropwise, 0.93 gr. freshly distilled aniline. Afterconcentration of the resulting solution a crystalline mass is obtained,from which the crystals are separated, centrifuged and recrystallised.These. crystals melt at 130-140 C. The yield amounts to 73%. 7

Example 13 2.16 gr. of 1-phenyl-2,3-dimethyl-5-pyrazolone aldehyde aredissolved in 3.5 cc. of a 2.92 N solution of sodium bisulphite. To theresulting solution of bisulphite compound are added 0.93 gr. of aniline,as in Example 12. After heating on a water bath during hour, anhomogenous solution is obtained, which is concentrated in vacuo. Thecrystals obtained melt at 130 C. with decomposition.

Example 14 describes the preparation of a bisulphite compound of theSchifis base of a 1,2,3-trisubstituted pyrazolone, the three reagentsbeing successively brought together.

Example 14 To a mol. of 1-phenyl-2,3-dimethyl-5-pyrazolone aldehyde aresuccessively added, a mol. of para-aminobenzene sulfonamide and acorresponding amount of a 2 N aqueous solution of natrium bisulphite.The resulting mixture is heated during 2 hours at 90 0., whereby a clearsolution is obtained, which is concentrated in vacuo. The crystalsobtained are recrystallised from water.

The bisulphite compound obtained has the empirical formula CmHwOaSzNaand contains 13.19% S, whereas the theoretical percentage of sulfur is13.50%.

The pharmacodynamic properties of this particular bisulphite compoundwere described hereinabove.

Examples 15 and 18 describe the preparation of bisulphite compounds byreacting natrium bisulphite with a Schiffs base of a1,2,3-trisubstituted pyrazolone.

The reaction for the production of such bisulphite compounds may berepresented as follows:

1 gr. of 1-phenyl-2,3-dimethyl-4-benzimino- -pyrazolone is dissolvedinto 13 cc. of ethyl alcohol. To the resulting solution 1 mol. ofnatrium bisulphite, in concentrated solution, is

added. The solution is concentrated in vacuo 8 at a low temperature,until the first crystals are formed, By cooling, the desired bisulphitecompound is first obtained. After centrifuging, this compound melts at-180" C. with decomposition and is soluble in ethyl alcohol and water. Asecond fraction precipitates subsequently and comprises unreactednatrium bisulphite.

Example 16 One mol. of 1,3g-diphenyl-2-methyl-4-benzimino-5-pyrazoloneis treated as described in Example 15. The bisulphite compound obtainedmelts at 120-125 C. with decomposition.

Example -1 7 Example 18 The Schiifs base, prepared by reacting1-pethoxyphenyl-2,3-dimethyl- 5 -pyrazolone aldehyde with4-amino-antipyrin, is treated as described in Example 15.

The bisulphite compound obtained melts at C. with decomposition.

It is understood that the invention is not exclusively'limited to theoperative methods described above and that modifiications can beintroduced into these,'both as regards the compounds used, theconditions and the proportions of the reagents, without departing fromthe field of the invention, as it is defined in the following claims.

What I claim is:

1 A new compound having the following formu- V J ULES HENRI THEOPHILELEDRUT. References Cited in thefile of this patent UNITED STATES PATENTSNluggger Name Date ,585 Ott et a1 Au 1, 1933 2,407,600 Bean Sept. 10,1946 FOREIGN PATENTS Number Country 7 Date 892,554 France Apr. 12, 1944OTHER REFERENCES

